The induction of matrix metalloproteinase and cytokine expression in synovial fibroblasts stimulated with immune cell microparticles

Distler, Jörg H W; Jüngel, Astrid; Huber, Lars C; Seemayer, Christian A.; Reich, Charles F.; Gay, Renate E.; Michel, Beat A.; Fontana, Adriano; Gay, Steffen; Pisetsky, David S.; Distler, Oliver

doi:10.1073/pnas.0409781102

Cited by 237 publications

(249 citation statements)

References 27 publications

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“…Studies suggest that Hcy might stimulate MMP9 expression via an NF-κB-activating mechanism, resulting in enhanced cytokine production [32] (NF-κB plays an essential role in the transcriptional activation of IL6 induced by various stimuli). Our finding that three different inhibitors of NF-κB activation reversed the Hcy-induced IL6 release in cells grown in low as well as high glucose is in keeping with this view, and the observation of a parallel inhibitory effect of both NAC and calphostin C on MMP release confirms a link between MMP and cytokine production [33].…”

Section: Discussionsupporting

confidence: 87%

High glucose and homocysteine synergistically affect the metalloproteinases–tissue inhibitors of metalloproteinases pattern, but not TGFB expression, in human fibroblasts

et al. 2006

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Aims/hypothesis Atherosclerosis is particularly aggressive in patients with diabetes. Hyperhomocysteinaemia causes oxidative stress and cytokine secretion: its atherogenic effect is mediated by an enhanced inflammatory response. Matrix metalloproteinases (MMPs) regulate extracellular matrix degradation and remodelling, and contribute to the vulnerability of the atherosclerotic lesion. Fibroblasts contribute to collagen biosynthesis and participate in plaque remodelling via expression and release of MMP2 and MMP9. To explore the role of hyperhomocysteinaemia in cellular pathways involved in plaque growth and stability in diabetic patients, we studied the effect of hyperhomocysteinaemia in human fibroblasts grown in the presence of normal or high glucose concentrations. Materials and methods In fibroblasts of five normal subjects, grown at 5.5 or 22 mmol/l glucose and treated with homocysteine, we determined: (1) MMP2, MMP9 and tissue inhibitor of metalloproteinases (TIMP)-1 (an MMP inhibitor) production by western blot analysis; (2) their activity by zymography; (3) TGFB1 expression by real-time PCR; and (4) TGFB, fibronectin and IL6 release by ELISA. Results Hyperhomocysteinaemia increased the production and enzymatic activity of MMP2 and MMP9, the effect being more pronounced in high glucose. Conversely, TIMP1 production was reduced by hyperhomocysteinaemia in both conditions, especially in high glucose. Hyperhomocysteinaemia also stimulated IL6 release, at least in part through nuclear factor-κB activation. TGFB1 expression was not affected by hyperhomocysteinaemia either in normal or in high glucose. Conclusions/interpretation Homocysteine upregulates the MMP-TIMP pathway and IL6 release, the effect being stronger in the presence of high glucose. These actions of homocysteine may contribute to the increased atherogenesis observed in diabetic patients with poor metabolic control.

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Section: Discussionsupporting

confidence: 87%

High glucose and homocysteine synergistically affect the metalloproteinases–tissue inhibitors of metalloproteinases pattern, but not TGFB expression, in human fibroblasts

et al. 2006

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“…To analyze whether microparticles derived from apoptotic ECs affect the number of CACs, CACs from patients with SSc and healthy volunteers were coincubated with microparticles for 4 days. The number of microparticles used for these experiments was based on the numbers of microparticles in the blood of patients with SSc and has also been used for other studies (22,23,29,30).…”

Section: Resultsmentioning

confidence: 99%

“…Apoptosis in primary human microvascular ECs (HMVECs; Invitrogen), immortalized HMVECs (27), and immortalized murine glomerular ECs (28) was induced by incubation with staurosporine (Sigma-Aldrich) at a concentration of 10 M. After 12 hours, supernatants were collected, and microparticles were isolated by differential centrifugation as previously described (23,29,30). For coculture experiments, CACs were incubated for 4 days with freshly isolated microparticles (1.0 ϫ 10 4 to 1.0 ϫ 10 5 ) derived from apoptotic ECs.…”

Section: Methodsmentioning

confidence: 99%

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Induction of apoptosis in circulating angiogenic cells by microparticles

Distler

Akhmetshina

Dees

et al. 2011

Arthritis & Rheumatism

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“…Total RNA was isolated with the NucleoSpin RNA II extraction system according to the instructions of the manufacturer (Machery-Nagel, Düren, Germany) and reverse transcribed into complementary DNA (cDNA) with random hexamers as previously described (21,22). Gene expression was quantified by TaqMan or SYBR Green real-time PCR using the ABI Prism 7700 Sequence Detection System (PE Applied Biosystems, Rotkreuz, Switzerland).…”

Section: Methodsmentioning

confidence: 99%

Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis

Distler¹,

Jüngel²,

Huber³

et al. 2007

Arthritis & Rheumatism

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363

273

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Objective. Imatinib mesylate is a clinically welltolerated small molecule inhibitor that exerts selective, dual inhibition of the transforming growth factor ␤ (TGF␤) and platelet-derived growth factor (PDGF) pathways. This study was undertaken to test the potential use of imatinib mesylate as an antifibrotic drug for the treatment of dermal fibrosis in systemic sclerosis (SSc).Methods. The expression of extracellular matrix (ECM) proteins in SSc and normal dermal fibroblasts was analyzed by real-time polymerase chain reaction, Western blot, and Sircol collagen assay. Proliferation capacity was assessed with the MTT assay. Cell viability was analyzed by mitochondrial membrane potential and by annexin V/propidium iodide staining. Bleomycininduced experimental dermal fibrosis was used to assess the antifibrotic effects of imatinib mesylate in vivo.Results. Imatinib mesylate efficiently reduced basal synthesis of COL1A1, COL1A2, and fibronectin 1 messenger RNA in SSc and normal dermal fibroblasts, in a dose-dependent manner. The induction of ECM proteins after stimulation with TGF␤ and PDGF was also strongly and dose-dependently inhibited by imatinib mesylate. These results were confirmed at the protein level. Imatinib mesylate did not alter proliferation or induce apoptosis and necrosis in dermal fibroblasts. Consistent with the in vitro findings, imatinib mesylate reduced dermal thickness, the number of myofibroblasts, and synthesis of ECM proteins in experimental dermal fibrosis, without evidence of toxic side effects. Conclusion. These data show that imatinib mesylate at biologically relevant concentrations has potent antifibrotic effects in vitro and in vivo, without toxic side effects. Considering its favorable pharmacokinetics and clinical experience with its use in other diseases, imatinib mesylate is a promising candidate for the treatment of fibrotic diseases such as SSc.

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The induction of matrix metalloproteinase and cytokine expression in synovial fibroblasts stimulated with immune cell microparticles

Cited by 237 publications

References 27 publications

High glucose and homocysteine synergistically affect the metalloproteinases–tissue inhibitors of metalloproteinases pattern, but not TGFB expression, in human fibroblasts

High glucose and homocysteine synergistically affect the metalloproteinases–tissue inhibitors of metalloproteinases pattern, but not TGFB expression, in human fibroblasts

Induction of apoptosis in circulating angiogenic cells by microparticles

Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis

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